Rhabdoviridae Viral Profiles:
Comparing Rabies and VSV
In the order Mononegavirales, Family Rhabdoviridae, there exist five
genera, two of which infect humans: Lyssavirus and Vesiculovirus.
Lyssavirus human pathogens include rabies virus and two rabies-like
viruses, Mokola and Duvenhage, that can cause human infection. Vesicular
Stomatitis is a disease caused by Vesiculovirus types 1-4 that is zoonotic
in humans and causes subclinical, flu-like infections.
Rhabdoviridae has a relatively long incubation period of 14-90 days, with
symptoms usually beginning 4-8 weeks after inoculation, although it may be
longer. For instance, in Australia there was a case in which the last
opportunity for infection occurred 6 years earlier.
Animal rabies is present in all continents except for Australia and
Antarctica. It is a disease with no natural reservoir,
transmitted via the saliva of infected mammals. The principal vector of
the virus is the dog although wild mammals can also infect humans, either
through direct bite or indirectly, via the infection of domestic animals.
The primary mode of transmission is through the bite of an infected
animal, albeit licking and scratching can also transmit the disease. In
some cases, rabies can be transmitted via aerosol (such as in bat caves)
or via corneal transplants from infected individuals.
In the U.S. bats are increasingly implicated as important wildlife
reservoirs and vectors of rabies. Recent epidemiological data suggest
that transmission of rabies can occur from minor or unrecognized bites
from bats. Since 1980 there have been 21 bat-associated cases of human
rabies out of a total of 36 cases in the continental U.S. (Hawaii remains
rabies-free). Foxes, skunks, raccoons and coyotes are also implicated
with rabies transmission. Fox rabies is enzootic in Western Europe and
North America. It is evident that rabies among wildlife has become more
prevalent since 1950, accounting for more than 85% of all reported cases
of animal rabies in the U.S. every year since 1976. Each year, roughly
16-39 thousand people receive post-exposure prophylaxis. In Latin
America, Africa, and Asia, dogs are the most common source of rabies
transmission to humans. In Latin America, vampire bats are also a problem
for humans and livestock. All in all, the World Health Organization
attributed >36,000 deaths world-wide to rabies in 1992. In regards to
VSV, it is a zoonotic disease transmissible from mammals to humans from
the vesicular fluids and tissues of infected animals. In humans it
resembles the flu, with the characteristic chills, fever, and muscle pain,
but in 7-10 days it runs its course without further complications.
Symptomology and Outcome
Rabies virus is neurotropic. Once rabies virus enters a suitable
host, it replicates in muscle and in cells of the subepitheleal
tissues until it reaches a sufficiently high concentration to infect
sensory and motor nerves in skin or muscle by binding to the
acetylcholine receptors and entering the nerve endings. Movement of
viruses within neuronal axons delivers virus to the Central Nervous
System, usually via the spinal column. An ascending wave of neuronal
infection and neuronal dysfunction later occurs. After a prodromal
phase of fever, malaise, and parasthesia around the site of infection,
the patient's muscles become hypertonic (stiff, rigid) and s/he
becomes anxious, with hydrophobia, hyperactivity, convulsions,
aggression, and eventually paralysis. Encephalitis is the most common
pathological effect. There are two possible clinical consequences of
rabies infection: "furious" or "dumb" rabies. When the virus reaches
the limbic system it causes "furious rabies" due to the extensive
proliferation of virus and the subsequent release of cortical control
of behavior. Once the infection reaches the neocortex it causes "dumb
rabies" as replication of virus here causes delirium, coma, and
eventually respiratory arrest and death.
Pathology and Pathogenesis
Rabies Virus and Vesicular Stomatitis Virus share many common structural
and functional characteristics, but they differ in their pathogenicity and
speed. The Lyssavirus family (Rabies) usually causes a slow, progressive
disease as compared with those of the Vesiculovirus family, which cause
acute, self-limiting infections. Lyssaviruses invade the Central Nervous
System producing encephalitis, while Vesiculoviruses tend to infect the
epithelial cell in organs such as the tongue, causing vesicles (hence the
name). Rabies can infect all mammals, while VSV has an even wider host
range, with the ability to infect horses, cattle, swine, humans, and even
insects. The VSV receptor recognized by neutralizing antibody is not a
protein, but rather believed to be phosphatidyl serine (according to
University of Rochester Medical Center web-site
www.urmc.rochester.edu/smd/mbi/grad2/nns99A.html; according to Fields,
Fundamental Virology 3rd
Edition,the receptor is the G protein, as in rabies virus). The
basis for the pathogenicity of VSV has been studied extensively and seems
to indicate that all vertebrate cells tested and to some degree,
invertebrate cells, are susceptible to infection. Replication occurs in
the cytoplasm, and assembly occurs through the budding off upon plasma
(vesiculoviruses) or intracytoplasmic (lyssaviruses) membranes. Rabies
virus produces conspicuous cytoplasmic inclusion bodies. VSV is often
referred to as inducing rapid Cytopathic Effects (CPEs) in vitro, although
it depends on the multiplicity of infection. At low doses of infection,
VSV is not seen for 24hrs or longer, but at higher concentrations, cell
rounding occurs in several hours. Within the first hours, VSV inhibits
cellular macromolecular synthesis, resulting in the shutdown of cellular
DNA, RNA, and protein production. In terms of genome, rabies is very
similar to VSV, both containing an unsegmented negative strand of RNA with
five to six genes in the order 3*-N-P-M-G-(X)-L 5*, but with the exception
that the intergenic regions are longer and more divergent in rabies virus,
and rabies also contains an untranslated pseudogene. This RNA is
associated with nucleocapsid protein composing the Ribonucleoprotein core
(RNP), the infectious component of VSV and rabies. In rabies, the major
receptor-binding molecule and antigenic determinants are the G protein
trimeric spikes on the surface which insert into cellular membranes and
allows fusion to occur. G protein undergoes a conformational shift at
pH<6.0 which stabilizes the trimer and exposes a hydrophobic domain that
can insert into cellular mebrane. Fusion occurs in the endocytic vesicle,
where there is acidic pH. Once the virus has adsorbed, penetrated,
uncoated, transcribed, replicated, assembled, and budded off the cell,
initiating a new round of infection by releasing more virus into nerves,
do the clinical symptoms appear that characterize rabies (see next
section). In VSV, only mild, flu-like symptoms are apparent.
- Prevention and Management
In countries where canine rabies is enzootic, the principle way to
control transmission of the disease to humans is via control of stray
dogs and cats, with quarantines enforced if deemed necessary.
Anti-rabies vaccination of dogs and cats, surveillance, and public
education measures are all important to ensure a halt to the spread of
disease. In nations such as the United States and Western Europe,
where wild animals are the principal vector of rabies, control of
wild-life rabies is more important, yet more difficult to achieve.
Oral administration of vaccine to foxes has been successful in
reducing the incidence of rabies in Western Europe.
Pre-exposure and post-exposure prophylaxis exists to treat actual or
potential rabies inoculation. Rabies prophylaxis consists of local
wound care, passive immunization, and active immunization.
Pre-exposure prophylaxis should only be given to individuals at risk
for contracting the virus such as laboratory personnel working with
rhabdovirus, veterinarians, animal control and wildlife workers, and
travelers to rabies-enzootic areas.
Types of Rabies Treatment
Two kinds of rabies treatment are currently available in the U.S.:
(1) Rabies vaccines
(2) Rabies Immune Globulin (RIG)
Rabies vaccines induce an active immune response that includes the
production of neutralizing antibodies. This humoral response usually
requires 7-10 days to develop and usually persists for at least two
years. RIG provides fast-acting, but passive immunity that persists
for only a short time (half-life is estimated at 21 days).
Vaccines licensed in the U.S.:
Currently there are four formulations of three inactivated rabies
vaccines licensed for preexposure and postexposure prophylaxis in the
(1) Human Diploid Cell Vaccine (HDCV)- prepared from the Pitman-Moore
strain of rabies virus grown on MRC-5 human diploid cell culture. It
is supplied either through Intramuscular (IM) Administration or
(2) Rabies Vaccine Adsorbed (RVA)- RVA is prepared from the Kissling
strain of Challenge Virus Standard (CVS) rabies virus adapted to fetal
rhesus lung diploid culture. RVA is adsorbed to aluminum phosphate
and is approved for IM administration only.
(3) Purified Chick Embryo Cell Vaccine (PCEC)- PCEC became available
in late 1997. It is prepared from the fixed rabies virus strain Flury
LEP grown in primary cultures of chicken fibroblasts. It is only
approved for IM administration.
The Fourth Formulation, Purified Duck Embryo Vaccine (PDEV) licensed
as Lyssavac N, is available only outside the United States.
All of the three aforementioned vaccines licensed in the Unites states
are considered to be equally efficacious.
Rabies Immune Globulin (RIG) Licensed in the U.S.:
There are two RIG products, Imogam-Rabies HT and BayRabTM. RIG is an
anti-rabies immunoglobulin preparation concentrated by cold ethanol
fractionation from plasma of hyperimmunized human donors. This rabies
neutralizing antibody is administered at 20 IU/kg body weight and is
used only in conjunction with vaccine during post-exposure therapy.
Post-Exposure Rabies Prophylaxis:
The principle components of rabies prophylaxis are wound treatment and
for previously unvaccinated individuals, the administration of the RIG
and vaccine. Persons bitten by a rabid animal should be given
post-exposure treatment immediately. In 1977, the World Health
Organization recommended a regimen of RIG and six doses of HDCV over a
three month period. Nowadays, one dose of RIG and five doses of HDCV
over a 28-day period has been found to be safe and effective in
inducing a humoral response. Trials with RVA and PCEC have been shown
to be equally as effective.
Treatment of Wounds:
Bite wounds should be washed thoroughly with soap, water, and a
virucidal agent. Thorough cleansing of the wound alone has been
proven to reduce the likelihood of rabies. Concurrent tetanus
prophylaxis and other bacterial control measures should also be
Post-exposure immunization should always include administration of
both passive antibody (RIG) and vaccine, with the exception of people
who have previously received complete vaccination regimens or those
who have been vaccinated with other vaccines and have documented
rabies antibody titers. These patients should only receive vaccine.
RIG is administer only once at the beginning of the antirabies
treatment to provide immediate antibodies until the patient responds
to one of the three vaccines by producing his/her own antibodies
(usually after the seventh day). It should be injected close to the
site of infection.
At the beginning of therapy any of the three vaccines approved in the
US (HDCV, RVA, or PCEC) can be administered along with RIG. A regimen
of five 1-mL doses should be administered intramuscularly: the first
immediately after infection occurs, and the remaining four doses on
days 3, 7, 14, and 28. In adults, the vaccine should always be
administered in the deltoid area intramuscularly, whereas in children
the thigh is also acceptable.
White, David O. and Frank J. Fenner. Medical Virology.
Press: San Diego, CA 1994.
Fields, Bernard et al. Fundamental Virology. Lippincott-Raven:
Philadelphia, PA 1996.
Center for Disease Control: http://www.cdc.gov.